DERIVAI AI ACIZILOR CHINOLONCARBOXILICI

FLUOROCHINOLONE

CLASIFICARE. STRUCTUR CHIMIC

Gen.
I

II

III

Reprezentant
ACID NALIDIXIC

NORFLOXACINA
CIPROFLOXACINA
LOMEFLOXACINA
OFLOXACINA

LEVOFLOXACINA
SPARFLOXACINA

Spectru antimicrobian
- Bacili G(-) (NU i Pseudomonas species)

- Bacterii G(-) (inclusiv Pseudomonas),

- Bacterii G (+) (slab pe Streptococcus pneumoniae)
- unii germeni atipici (micoplasme, chlamidii)
-

IV

CLINAFLOXACINA*
GATIFLOXACINA*
MOXIFLOXACINA*
TROVAFLOXACINA
ALATROFLOXACINA

Generaia a II-a +
Germeni penicilino-rezisteni
Germeni patogeni atipici (micoplasme, chlamidii,
ureaplasme, legionella)
Mycobacterii (tuberculosis, M.avium intracelulare)

Generaia a III-a + anaerobi

DERIVAT DE NAFTIRIDIN

DERIVAI DE CHINOLIN

O
F

COOH
H3C

NORFLOXACINA

HN

COOH

C2H5

C2H5

ACID NALIDIXIC

O
F
CIPROFLOXACINA

R5

R6
R7

HN

COOH

COOH
X

R8

R1

O
CH3
LOMEFLOXACINA

HN

COOH

N
F

STRUCTURA GENERAL

C2H5
O

F
OFLOXACINA

H3C N

COOH

N
O

CH3

F
H3C N

COOH

N
O

H2N

LEVOFLOXACINA

CH3
HN

CLINAFLOXACINA
O

O
F

COOH

COOH

N
CH3

N
Cl

CH3

NH2

COOH

HN

N
F

N
OCH3

CH3

GEN. A IV-A

GATIFLOXACINA

SPARFLOXACINA

O
F
H
N

COOH

N
OCH3

GEN. A III-A

MOXIFLOXACINA
O
F
N

COOH
N

H2N
F

F
TROVAFLOXACINA

OBINEREA CIPROFLOXACINEI
Cl

Cl

+ CH2(COOC2H5)2

F
1
TsOH
- CO2
-C2H5OH

Cl

Cl
F

CO

CO

CH - HN
C - COOC2H5

NaH Cl
F

N
F

COOH
7

CH - OC2H5
C - COOC2H5

N
COOH
6

NH
HN

CO

Cl

Cl

Cl

HC(OC2H5)3 Cl
CH2COOC2H5

CH(COOC2H5)2

CO

HN

(H5C2O)2Mg Cl

COCl

H2N

Cl

MECANISM DE ACIUNE

Legare de ADN

Legare de
enzim

Legare de
enzim

Autoasamblare

4 molecule

Aciune chelatant
CH2 - CH3
H3C

N
C

CH2 - CH3
H3C

N
C
O

O
complex 2:1

Me

Me
complex 1:1

O
C

H3C

N
CH2 - CH3

REZISTENA LA FLUOROCHINOLONE

POMP DE EFLUX

REDUCEREA
PERMEABILITII

MUTAII

SPECTRU DE ACTIVITATE - bactericid + bacteriopauz (post-antibiotic)

Generaia I-a - Acid nalidixic exclusiv bacili G(-). Nu Pseudomonas aeruginosa

FLUOROCHINOLONELE (gen. II-IV)

Coci G(+) - + stafilococi rezisteni la meticilin i gentamicin, streptococi rezisteni la

peniciline
-Trovafloxacina > Grepafloxacina > Sparfloxacina > Levofloxacina
-Pneumococii sunt mai puin sensibili
Coci G(-) - Neisseria gonorrhoea
Bacili G(+) - Listeria monocytogenes meningite (vrstnici sau imunodeficitari)
Bacili G(-) - Escherichia coli, Salmonella, Shigella, Klebsiella, Proteus, Providencia sp.,
Haemophylus influenzae, Acinetobacter
-Pseudomonas aeruginosa
Ciprofloxacina>levofloxacina>trovafloxacina>gatifloxacina>moxifloxacina

SPECTRU DE ACTIVITATE (continuare)

Bacterii atipice (dezvoltare intra-celular)

- Legionella
- Chlamidia trachomatis (foarte active)
- Mycoplasma pneumoniae
- Ureaplasma urealyticum
Mycobacterii (tuberculosis, leprae) gen. III, IV
Bacterii anaerobe (gen. IV)
- Trovafloxacina - Bacteroides fragilis,Peptostreptococcus sp.,
Prevotella sp.
- Gatifloxacina - 4-16 > ciprofloxacina Clostridii,
Bacteroides

RELAII STRUCTUR SPECTRU DE ACTIVITATE

CH3: G(+)
NH2: G(-)
R5

HN

G(-)

R7

COOH
X8

N
R1

G(+)

Anaerobi

F
N

H2N

Micobacterii
G(-)

G(+)

Anaerobi
Micobacterii

Anaerobi

C(CH3)3
F

OCH3

PROPRIETI FARMACOCINETICE - FQ
Absorbie i biodisponibilitate
-rapid i aproape complet (1 or), nemodificat semnificativ de
ctre alimente
-legare 10-40% de proteinele plasmatice
Distribuie - larg, practic n toate esuturile, Vd mari (exceptie
NORFLOXACINA concentratii serice scazute)
-esut prostatic i lichid seminal
-parenchim renal
-esut muscular, esut osos
-sfera ORL, glande salivare, secreie bronic
-tract genital
-T1/2 4-12 ore + efect post-antibiotic
-Metabolizare hepatic, inhibitori Cyt P450
-Eliminare - renal, biliar, hepatic ca atare sau metabolii

INDICAII TERAPEUTICE. MOD DE ADMINISTRARE

Acid nalidixic (NEGRAM, NEGRAM FORTE)

-cp. 500mg, 1g 4 g/zi (4 prize), 1-2 spt

-infeciilor urinare acute, cronice i recidivante necomplicate

-terapie postoperatorie pe cile urinare, dup manevre endoscopice

sau la purttori de sonde urinare
Norfloxacina
-absorbtie 30-40%, T1/2=3-4 ore
-terapia infeciilor urinare (preponderent)
-infectii digestive (salmonella, shigella, Vibrio spp., E.coli).

INDICATII - FLUOROCHINOLONE gen II-IV

Infecii ale tractului urinar i genito-urinar
-cistit necomplicat 3 zile
-pielonefrite - 7-10 zile
-prostatite bacteriene (norfloxacina, pefloxacina, ofloxacina, sparfloxacina) 7 zile
-infecii gonococice
-ancru moale - ciprofloxacin (3 zile)
Infecii intestinale
-diaree 3 -10 zile
-eradicarea purttorilor cronici de Salmonella typhi

Infecii ale pielii i esuturilor moi

Utilizarea n osteomielite i artrite septice 4-6 sptmni

INDICATII - FLUOROCHINOLONE gen II-IV (continuare)

Infecii ale cilor respiratorii (medicamente de alternativ)
-Tuberculoz multirezistent, infecii cu Mycobacterium avium complex (bolnavi de SIDA)
-ciprofloxacina, ofloxacina, levofloxacina, moxifloxacina, sparfloxacina
-Meningite germeni aerobi (Pseudomonas) sau anaerobi Sparfloxacina
- Infecii ORL - otite medii (acute i cronice), amigdalite, sinuzite (acute i cronice) 7 zile
- Infecii oftalmologice (100-200 mg de 2-3ori/zi)

DCI

Specialiti

Forme farmaceutice
cp. 400 mg, sol.oftalmic, 2x400 mg/zi

NORFLOXACIN, NOLICIN- cp
CHIBROXIN sol.oft.

-cp. film. 250-500-750 mg (1 cp la 12 ore)

-sol. perfuzabil 50 mg/100ml
-Colir

CIPROBAY cp., sol.perf.

EUCIPRIN, CIPROLEN (Ro) cp.
CILOXAN (Belgia) colir

- cp. 200 mg, 400 mg

- sol.perfuzabil 200 mg/100ml
- 200 mg la 12 ore, 400 mg la 24 ore

OFLOXACIN, ZANOCIN

Levofloxacina

- cp. 250 mg, 500 mg

- sol.perf. (fl. 250, 500 mg)
-500 mg/zi

LEVAQUIN (Frana)

Sparfloxacina

- cp. film. 200 mg (200 mg/zi)

ZAGAM (Rohne-Poulenc Rorer)

Gatifloxacina

- cp. 400 mg, sol. perf. (fl. 400 mg)

-400 mg/zi

TEQUIN (Bristol-Myers Squib)

Moxifloxacina

- capsule 200 mg (200 mg/zi)

AVELOX

Trovafloxacina

-cp. 100 mg, 200 mg

-(100-200 mg/zi)

TROVAN (Pfizer, SUA)

Lomefloxacina

-Colir 0,3%, 1 pic. la 12 ore

-Picturi pentru urechi 0,3%
-Comprimate 400 mg (1 cp la 12 ore)

OKACIN, LOMADAY

Norfloxacin

Ciprofloxacina

Ofloxacina

EFECTE SECUNDARE. REACII ADVERSE

- Tulburri gastro-intestinale - anorexie, gastralgii, grea, vomismente, diaree
- Tulburri neurologice: cefalee, ameeli, convulsii, etc
- Fototoxicitate, fotosensibilizare
- Efecte secundare la nivelul articulaiilor i cartilajelor (exceptie acidul nalidixic)
-Efecte secundare la nivel renal cristalurie (norfloxacin, ciprofloxacin)
-Efecte secundare la nivel cardiac - sparfloxacina, gatifloxacina, moxifloxacina)
- Leucopenie, trombocitopenie

CONTRAINDICAII
-gravide - anemie hemolitic, acidoz metabolic sever a nou-nscutului, afectare
a cartilagiilor
-copii cu vrsta mai mic de 18 ani (levofloxacina, fluorochinolone gen. a IV-a)
-Pacieni cu deficit de G-6PDH
-Pacieni cu epilepsie
PRECAUII
-insuficien hepatic i tratament asociat cu anticoagulante
-insuficien renal
-conductori auto
-evitarea expunerii la radiaii UV
-Pacieni cu aritmii cardiace

RELAII STRUCTUR- TOXICITATE

Potential convulsivant

Legare de receptori
GABA
Penetrare SNC

R5

F
HN
R

COOH

R7

X8

Inhibarea CytP450

N
R1

C2H5

Fototoxicitate
N
F

H2N
Substituenti
putin voluminosi

Inhibarea CytP450

>

Cl

>>

OCH3

INTERACIUNI
NU SUNT BENEFICE SAU SE ADMINISTREAZ CU PRECAUIE
-Compui ce conin metale bivalente i/sau trivalente - SPAIERE 2-4 ore
-Medicamentele antiacide
-Medicamentele antianemice (sruri de fier)
-Produse lactate
-Ioni complexani n urin cristalurie
-Medicamente anticoagulante crete efectul anticoagulant
-Medicamente cu structur xantinic - (cafein, teofilin) - risc convulsiv
-Benzodiazepine (diazepam, alprazolam, etc) - risc convulsivant
-AINS (diclofenac, ibuprofen) efect redus risc convulsivant
-Antibiotice ce inhib sinteza proteic (cloramfenicol), tetracicline ef. antagonic
-Derivai de nitrofuran interaciune chimic + efect antagonic
ASOCIERI BENEFICE
-Antibiotice: beta-lactamine, aminoglicozide, polimixine, sulfamide ef. sinergic